Microwave-assisted synthesis and functionalization of 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones

Despite the limited applications and scarcity of commercial examples of imidazo[1,2-a]pyrimidines, their exceptional properties hold great potential, representing a significant challenge in discovering more critical applications. Herein, we present a microwave-assisted approach for preparing 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones and their alkylation and bromination products using easily accessible and inexpensive reagents, thus offering a promising avenue for further search. Notably, the photophysical properties of an N-alkyl derivative were investigated, and the results highlight the high potential of these compounds as modular fluorophores. All the products were obtained with high yields using highly efficient protocols, and the regioselectivity of the reactions was determined on the basis of NMR measurements and X-ray diffraction analysis.


Results and discussion
Synthesis of 2-arylimidazo[1,2-a]pyrimidinones 4a-e First, a-bromoacetophenones 2a-e were prepared by known protocols using acetophenones 7a-e and bromine in polar solvents; 37,38 Amberlite MB-1® (0.1 g mmol −1 of 7) was used as a solid catalyst support to obtain the best feasible results (Scheme 3a).Meshram et al. 46 used NBS and Amberlyst-15® (like-reticular resin for acidic catalysis) under similar reactions, but we used bromine (Br 2 ) as it is cheaper than NBS.Both are ion-exchange resins of polystyrene-divinylbenzene; however, gel-like Amberlite MB-1® has amphoteric properties and is usually used in chromatography and synthesis.Products were obtained with quantitative yields because perhaps bromine and its residues were easily encapsulated in this resin, favoring the reaction and product isolation. 47Then, by a standard MWassisted route, we carried out the reaction of 2a-e with 3 (1 equiv.) to obtain 2-arylimidazo[1,2-a]pyrimidinones 4a-e (Schemes 3b).In this way, we reproduced the synthesis of 4a (Ar = Ph) by Laneri et al. (they obtained an 80% yield using 2.5 equiv. of 3) 43 but with poor yield using 1 equiv. of 3 (Scheme 3b, test 1).However, we heated the reaction mixture under MW at 160 °C, and product formation was observed aer 20 minutes with moderate yield (50%, test 3 vs. 2).Then, the reaction mixture was heated at 180 °C, and the reagents were consumed aer 20 minutes, forming 4a with a 84% yield (test 5 vs. 4).With a focus on lowering the temperature, the reaction mixture was heated from 100 to 160 °C for a longer time (40 and 60 min), and the reagents were consumed aer 60 minutes at 100 °C and 40 min at 160 °C, producing 4a with a 82% yield (test 6 to 11).Thus, 160 °C and 30 minutes under MW conditions were considered the optimal reaction conditions (test 11).Finally, although 4a can be obtained by reuxing in DMF, this method was revised due to poor yield and the need for an excess of 3, which is a highly insoluble reagent that decomposes under these conditions.
The reaction scope was examined using an equimolar mixture of 6-methylisocytosine (3) and a-bromoacetophenones 2a-e (1 mmol) under MW heating at 160 °C for 20 minutes.This reaction yielded 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones 4a-e with high yields as white-yellow solids that had high melting points (Scheme 4).Notably, pure products were obtained when the reaction mixture was treated with water (3 mL), the deposited solid was collected by simple ltration, washed with cold ethanol (2 × 2 mL), and placed under a high vacuum for one hour at 60 °C.In addition, almost no loss of reaction efficacy was observed with the a-bromoketones tested, evidencing that the electronic nature of the substituent in the phenyl ring had little effect on the reactivity of 2a-e.However, the lowest yield was observed for 4e as the reaction mixture turned dark when the nitrosubstituted substrate 2e was used, which may be due to its high polarity.These results suggest the feasibility of improving the synthetic method of 4a-e using sustainable protocols (i.e., ecological, social, and economic scopes) compared with other reported synthetic methods.

Functionalization of the 2-arylimidazo[1,2-a]pyrimidinones 4a-e
Although the solubility of the 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones 4a-e in organic solvents was better than that of 6methylisocytosine (3), it was still too low to favor its reactivity in further synthesis.Thus, with 4a-e in hand, we envisaged that their N-alkylation reaction with alkyl bromines 5a-c (1 equiv.)under microwave irradiation (15 min) could be used to prepare 8-alkyl-2-arylimidazo[1,2-a]pyrimidinones 6a-o.We optimized this reaction by synthesizing the N-propyl derivative 6a using 4a and n-propyl bromide (5a) as the model reagents (Table 1).The effect of cesium in promoting MW-assisted reactions 48 and its value in preparing products that are highly soluble in organic solvents, such as 6a-o, are well-known; 14 however, we wanted to implement an efficient protocol by involving a base cheaper than Cs 2 CO 3 (i.e., NaH, tBuOK, Na 2 CO 3 , or K 2 CO 3 ) in lower quantity (1 equiv.)and using the minimum amount of aprotic solvent (i.e., MeCN, DMSO, or DMF).In this optimization experiment, the best results were obtained when the reaction was carried out in dry DMF at 150 °C using potassium carbonate as the base (entry 7 vs. 1 to 6).
Subsequently, the substrate 5a and the potassium carbonate equivalents were doubled, the temperature was reduced, and the reaction time was increased (entries 8 to 12, Table 1); in these experiments, the best results were obtained when the reaction was carried at 100 °C for 15 minutes (entry 10).Ultimately, the equivalent amounts of the substrate and base were reduced to 1.5, which afforded the optimal results at 100 °C for 15 minutes in DMF as the solvent (entry 13).However, good results were obtained when the reaction was carried out at 60 °C for 1 hour and even in acetonitrile as the solvent at 100 °C (entries 12 and 15).Therefore, with the optimal conditions in hand to form 6a, we investigated the scope of the N-alkylation reaction for 4a-e using alkyl bromides 5a-c (Scheme 5).In general, the reaction showed excellent tolerance of reagents, resulting in the desired products 4a-o as colorless solids with outstanding yields (>73%).In addition, the conditions used for obtaining the precursors and products are better than those for reported IPs (i.e., 4a-e and 6b, 6g, and 6l).
Once the IPs 6a-o were obtained, the practical utility of this approach in medical and synthetic chemistry settings was explored.Specically, the preparation of the anticancer agent ethyl 2-(4-chlorophenyl)-7-methyl-5-oxoimidazo[1,2-a] pyrimidine-8-acetate (6p) and the reactivity of the rings in 6ae in the bromination reaction were evaluated (Scheme 6).Notably, Kawaguchi et al. 14 have identied ester 6p (Hit A) as a potent and selective autotaxin (ATX) inhibitor that rescues the ATX-induced cardia bida phenotype in zebrash embryos.They obtained 6b and other N-alkyl derivatives by an approach similar to that used for 6a-o (see Scheme 2a); however, our standard MW-assisted approach proved more efficient in various aspects (Schemes 4-6a).MeCN 67 a Reactions conditions: 4a (0.25 mmol) and 5a/base (1 equiv.).Experiments performed in 10 mL sealed tubes under MW in 0.5 mL of the solvent.NR = no reaction.b 5a/base (2 equiv.).c 5a/base (1.5 equiv.).
Furthermore, the reactivity of 6a-e was successfully evaluated by a simple bromination reaction.The imidazo [1,5-a]  pyrimidine ring can react with electrophiles at two places, but the p-excessive nature of imidazole favors position 3 over 6 in the pyrimidine core.Most electrophilic aromatic substitution (EAS) reactions lead to 3-substituted products, [18][19][20][21]43 but the alkyl group in 6a-e played a crucial role in their reactivity. Inded, 3,6-dibrominated IPs 8a-e were easily obtained, while directed regioselectivity could not be achieved despite strict control of the reaction conditions.For example, in the NMR and HRMS analyses of the reaction crude of 6b with 1 equiv. of bromine at 0 °C for 10 min, a mixture of compounds was observed (i.e., 8b > 6-Br6b > 3-Br6b > 6b), evidencing the high reactivity of 6b and its preference to form the dibrominated product 8b.As a result, by using 2 equiv. of bromine for 1 hour at room temperature, compounds 8a-e were efficiently obtained (Scheme 6b).This type of compound would be useful in Pdcatalyzed C-C cross-coupling reactions, [18][19][20][21] and the reaction approach may spearhead future syntheses based on EAS reactions of the imidazo[1,2-a]pyrimidine ring.
The structures of the compounds obtained were elucidated by HRMS analysis and 1 H and 13 C NMR spectroscopy, including some two-dimensional methods (see experimental processes, characterization data, and NMR spectra in ESI †).Gratifyingly, recrystallization of the 3,6-dibromoimidazo[1,5-a]pyrimidine 8b from a chloroform-methanol mixture (1 : 1 v/v) afforded crystals of suitable size and quality for single-crystal X-ray diffraction analysis (Scheme 6b). 49n the other hand, we performed a preliminary photophysical study of the 2-(4-methoxyphenyl) derivative 6i to establish the scope of the imidazo[1,5-a]pyrimidine heterocyclic core as an organic uorophore due to its limited exploration [9][10][11] and our wide interest in this eld (Fig. 2 and Table 2). 7,8This study was conducted to classify compounds 6a-o as strategic intermediates of novel functional uorophores due to their high synthetic viability.][11] The UV-vis and uorescence emission spectra of 6i were achieved in six solvents with different polarities, including cyclohexene (CH), t-butyl methyl ether (TBME), dichloromethane (DCM), ethyl acetate (AcOEt), N,N-dimethylformamide (DMF), and acetonitrile (MeCN); the results are shown in Fig. 2 and Table 2. Cyclohexene was used as the lowest polarity solvent since 6i is highly insoluble in alkanes (e.g., cyclohexane).The absorption spectra of 6i displayed two typical bands, one at 280 nm attributed to the p / p* transitions and the other at As a result, the polarity of the microenvironment moderately inuenced the photophysical properties of 6i (Fig. 2a).Fluorophore 6i displayed large Stokes shis (7474-8658 cm −1 ) without a specic solvatouorochromic shi in the six evaluated solvents; however, 6i exhibited appreciable uorescence intensity (f F of up to 0.18), and the highest uorescence quantum yield (f F ) and brightness (B = 3 × f F = 2286) values were achieved in a medium-polarity solvent AcOEt (Fig. 2b and Table 2).From these results, we can establish that the heterocyclic core of imidazo[1,2-a]pyrimidine is a promising functional uorophore for application in detection chemistry, diagnostic bioimaging, and photosensitizers.

Conclusions
In summary, 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones 4a-e and their N-alkylation 6a-o and 3,6-debromination 6a-e products were successfully synthesized with high yields through microwave-assisted reactions using easily accessible and inexpensive reagents.All the obtained compounds were characterized by HRMS spectroscopy and NMR analysis, and the structure of the nal product (8d) was conrmed by singlecrystal X-ray diffraction analysis.The synthetic utility of the alkylation reaction was further proven by synthesizing the anticancer drug 6p (Hit A).Notably, 6a-o were more soluble in organic solvents than their precursors 4a-e, thus expanding the applicability of this type of heterocyclic compound.Indeed, this was veried by the straightforward synthesis of 8a-e; however, it is worth studying the reactivity of the N-heterocyclic ring further to achieve more regioselectivity of the substituents on its periphery.In addition to the synthetic and biological applications of 6a-p, the remarkable photophysical properties exhibited by 6i highlight the high potential of these compounds as modular uorophores.

Table 1
Optimization of the synthesis of the 2-phenyl-8-propyl derivative 6a a